1. Field of the Invention
This invention relates to new compounds useful for inhibiting the formation of blood clots, or dissolving blood clots after they have been formed, and more particularly to novel alkylenetris- and alkylenetetrakis-[1,2,3,4-tetrahydroisoquinoline] and -[3,4-dihydroisoquinoline] compounds, and the pharmaceutically acceptable acid addition salts thereof.
2. Description of the Prior Art
In the formation of a blood clot, for example a thrombus, fibrinogen, a soluble plasma protein, is converted to the insoluble protein fibrin. As the fibrin is deposited it entraps blood cells within its meshwork to form a coagulum. In the case of a thrombus, the coagulum usually interferes with the flow through the blood vessel.
The defense of the living organism against such occurrence is the plasma protein called plasminogen which, under certain conditions, can be activated by an "activator" whereby the plasminogen is converted to the protein, plasmin. Plasmin possesses the property of efficiently digesting and destroying fibrin (fibrinolysis). The fibrinolysis results in dissolution of the clot, and, in the case of a thrombus, restores the patency of the vessel.
Under normal conditions, the organism has low levels of "activator" in the blood stream. It is believed that small amounts of plasminogen are constantly undergoing conversion to plasmin by the action of the "activator". However, from a quantitative viewpoint, the amount of activator normally present in insufficient to produce enough plasmin to lyse the relatively large amount of fibrin present in a clot such as a thrombus.
Fibrinolytic activity in vitro is manifested by many compounds such as the aromatic sulfonic acids, derivatives of salicylic acid, long chain fatty acids and halogenated unsaturated acids. Such compounds have not, however, been found to exhibit in vivo fibrinolytic or thrombolytic activity.
Fibrinolytic activity in vivo can be induced by nicotinic acid, procaine, phenylbutazone, acetylcholine, epinephrine, serotonin and histamine. However, the effect of these compounds is of short-lived duration, i.e., of the order of minutes.
Some sulphonylureas and steroids can induce an increase in fibrinolytic activity, but a lag period of the order of hours precedes the slow increase in lytic activity. Compounds of this type cannot be used when a substance is employed to effect thrombolytic therapy, because in such instance the activity must be rapidly induced to be effective in dissolving clots.
Streptokinase, a streptococcal protein, has been used for thrombolysis, but the side effects of pyrogenicity and anaphylactic reactions have limited its use.
Urokinase, a protein isolated from human urine, has also been used for thrombolysis but the difficulties involved in accumulating large supplies of the starting material, human urine, and the great cost of preparing the substance has proscribed its general and practical utility.
Bacterial pyrogens have also been used to effect thrombolysis, but the severity and unpredictability of the pyrogenic reactions have negated their usefulness.